Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
  • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

• the present invention relates to new derivatives of taxol analogs of general formula:
• Ar represents an aryl radical
• R represents
• R 7 represents a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 10 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy, alkoxy radicals containing 1 to
• cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms,
• R 1 and R 2 identical or different, represent a hydrogen atom or a radical of general formula: (m)
• R 3 and R 4 identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms in an optionally substituted straight or branched chain:
• R 5 and R 6 identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain, or else R5 and R ⁇ form together with the nitrogen atom to which they are linked a saturated or unsaturated 5 or 6-membered heterocycle optionally containing a second heteroatom chosen from nitrogen atoms (optionally substituted by an alkyl radical containing 1 to 4 carbon or benzyl atoms), oxygen or sulfur, or else R 3 and R 4 form together with the nitrogen atom to which they are linked a saturated or unsaturated 5 or 6-membered heterocycle optionally containing a second heteroatom chosen from nitrogen atoms (optionally substituted by a alkyl radical containing 1 to 4 carbon or benzyl atoms), oxygen or sulfur, it being understood that at least one of the symbols R 1 or R 2 represents a radical of general formula (III).
• Ar represents a phenyl or ⁇ - or ⁇ -naphthyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, alkenyl, alkynyl, aryl radicals, arylalkyls, alkoxy, alcoylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, carbamoyl, dialcoylcarbyl, carboxyloyl, carboxyloyl, carboxyloyl, carboxyloyl, carboxyloyl, carboxyloyl, carboxyloyl, carboxyl
• Ar represents a phenyl radical optionally substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and alkyl, alkoxy, amino, alkylamino, dialkoylamino, acylamino, alkoxycarbonylamino and trifluoromethyl radicals.
• Ar represents a phenyl radical optionally substituted by a chlorine or fluorine atom, or by an alkyl (methyl), alkoxy (methoxy), dialkoylamino (dimethylamino), acylamino (acetylamino) or alkoxycarbonylamino (tert-butoxycarbonylamino) radical. .
• the new derivatives of taxol analogs of general formula (I) can be obtained by the action of an amine of general formula (I).
• G 1 and G 2 each represent a radical of general formula (III) or a protective group (CCI 3 CH 2 OCO-), it being understood that at least one of the radicals G 1 and G 2 represents a radical of general formula (III), followed, if necessary, by the replacement of the protective group or groups (CCI 3 CH 2 OCO-) with a hydrogen atom.
• the action of the amine of general formula (V) on the taxane derivative of formula (VI) is carried out in an inert organic solvent such as a halogenated aliphatic hydrocarbon such as methylene chloride at a temperature between 0 ° C and the boiling temperature of the reaction mixture.
• an inert organic solvent such as a halogenated aliphatic hydrocarbon such as methylene chloride
• a halogenated aliphatic hydrocarbon such as methylene chloride
• a mixture of the products of general formula (VII) is formed in which one of the radicals G 1 or G 2 represents a radical of general formula
• the replacement of the protective group represented by G 1 or G 2 is generally carried out by treatment with zinc in acetic acid, optionally in the presence of methanol at a temperature between 30 and 80 ° C.
• the product of general formula (I) obtained by the process according to the invention can be purified by physical methods such as crystallization or chromatography on an appropriate support.
• the product of general formula (I) can optionally be transformed into an addition salt with mineral acids (hydrochloric, sulfuric, nitric, phosphoric acids) or organic acids (acetic, oxalic, maleic, fumaric acids).
• the reaction medium is heated with stirring for 3 hours at a temperature in the region of 60 ° C, then cooled to a temperature in the region of 20 ° C and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• 5.3 g of a white meringue are obtained which is purified by chromatography on 150 g of silica (0.063-0.2 mm) contained in a column 4 cm in diameter [eluent: dichloromethane-methanol (95-5 by volume)] by collecting fractions of 100 cm3. Fractions 1 to 10 are eliminated, then the chromatography is continued, eluting with a mixture: dichloromethane-methanol (80-20 by volume).
• Fractions 17 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C. 2.57 g of a mixture are thus obtained in molar proportions: 66/33 of the two substitution derivatives, [(3-dimethylamino propyl) carbamoyloxy] -, respectively in position 10 and 7.
• the support can be prepared as follows: In a 6 liter three-necked flask, 600 g of aminopropyl silica (100 ⁇ - 10 ⁇ m - NH 2 ; Macherey-Nagel) are suspended in 2 liters of dimethylformamide. 95 g of N-tert-butoxycarbonylamino-11 undecanoic acid anhydride are added and the reaction mixture is stirred for 18 hours at a temperature in the region of 20 ° C. The silica is separated by filtration and washed successively with twice 1500 cm3 of dichloromethane then twice 1500 cm3 of dimethylformamide.
• the silica thus washed is resuspended in 2 liters of dimethylformamide and 95 g of N-tert-butoxycarbonylamino-11 undecanoic acid anhydride are added, then the reaction mixture is stirred for 18 hours at a temperature in the region of 20 ° C .
• the silica is separated by filtration, washed successively twice
• the silica is separated by filtration and washed successively with twice 1 liter of dichloromethane, twice 1 liter of a dichloromethane / diisopropylethylamine mixture (70/30 by volume), 1 liter of dichloromethane, twice 1 liter of tetrahydrofuran, twice 1 liter of methanol and twice 1 liter of diethyl ether then dried under reduced pressure to a temperature close to 50 ° C.
• the silica thus washed and dried is resuspended in 2 liters of a 6% by volume solution of trifluoroacetic acid in dichloromethane.
• the reaction mixture is stirred for 16 hours at a temperature in the region of 20 ° C.
• the silica is separated by filtration and washed successively twice
• the silica thus washed is resuspended in 2 liters of dimethylformamide and 30 g of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydro-quinoline and 42 g of 3,5-dinitro-3,5-benzoyl-D-phenylglycine are added and then the reaction mixture for 5 hours at a temperature in the region of 20 ° C.
• the silica is separated by filtration, washed successively with twice 1 liter of dimethylformamide, twice 1 liter of dichloromethane, twice 1 liter of tetrahydrofuran, twice
• silica "DNB-D- Phg-C 11 -C 3 -silica-O-Si (CH 3 ) 2 (CH 2 ) 7 CH 3 " are suspended. liter of dichloromethane and 100 cm3 of dimethyloctylmethoxysilane are added, then the reaction mixture is stirred for 54 hours at a temperature in the region of 20 ° C. The silica is separated by filtration, washed successively with twice 1 liter of dichloromethane, twice
• N-tert-butoxycarbonylamino-11 undecanoic acid anhydride can be prepared as follows:
• N-tert-butoxycarbonylamino-11 undecanoic acid can be prepared according to the method described by J.T. SPARROW, J. Org. Chem., 41.1350 (1976).
• reaction mixture is then stirred for 1 hour 30 minutes at 60 ° C then cooled to a temperature in the region of 20 ° C and filtered through sintered glass lined with celite.
• the sintered glass is washed with 3 times 5 cm 3 of dichloromethane and the filtrates are combined and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C.
• reaction mixture is then stirred for 1 hour 30 minutes at 60 ° C then cooled to a temperature in the region of 20 ° C and filtered through sintered glass lined with celite.
• the sintered glass is washed with 3 times 5 cm3 of dichloromethane and the filtrates are combined then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature close to
• reaction medium is heated with stirring for 3 hours at a temperature in the region of 60 ° C, then cooled to a temperature in the region of 20 ° C and concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C.
• 0.32 g of a white meringue is obtained which is purified by chromatography on 30 g of alumina (0.12-0.15 mm) contained in a column 1.5 cm in diameter [eluent: dichloromethane -methanol (95-5 by volume)] by collecting 10 cm 3 fractions.
• Fractions 7 to 15 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 ° C.
• the new products of general formula (la) present particularly interesting biological activities.
• the new products of general formula (la) show a significant inhibitory activity against abnormal cell proliferation and have therapeutic properties allowing the treatment of patients with pathological conditions associated with abnormal cell proliferation.
• Pathological conditions include abnormal cell proliferation of malignant or non-malignant cells of various tissues and / or organs including, but not limited to, muscle, bone or connective tissue, skin, brain, lungs, sexual organs, lymphatic or renal systems, mammary or blood cells, liver, digestive system, pancreas and thyroid or adrenal glands.
• pathological conditions may also include psoriasis, solid tumors, ovarian, breast, brain, prostate, colon, stomach, kidney or testicular cancer, Kaposi's sarcoma, cholangio-carcinoma, choriocarcinoma, neuroblastoma, Wilms tumor, Hodgkin's disease, melanomas, multiple myelomas, chronic lymphocytic leukemias, acute or chronic granulocytic lymphomas.
• the new products according to the invention are particularly useful for the treatment of cancer of the ovary.
• the products according to the invention can be used to prevent or delay the onset or recurrence of pathological conditions or to treat these pathological conditions.
• the products according to the invention can be administered to a patient in different forms adapted to the chosen route of administration which, preferably, is the parenteral route.
• Parenteral administration includes intravenous, intraperitoneal, intramuscular or subcutaneous administration. More particularly preferred is intraperitoneal or intravenous administration.
• the present invention also includes pharmaceutical compositions which contain at least one product of general formula (Ia) in a sufficient amount suitable for use in human or veterinary therapy.
• the compositions can be prepared according to the usual methods using one or more pharmaceutically acceptable adjuvants, carriers or excipients. Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents.
• Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents.
• the compositions are in the form of aqueous solutions or suspensions, injectable solutions which may contain emulsifying agents, dyes, preservatives or stabilizers.
• adjuvants or excipients can be determined by the solubility and chemical properties of the product, the particular mode of administration and good pharmaceutical practices.
• aqueous or non-aqueous sterile solutions or suspensions are used.
• non-aqueous solutions or suspensions can be used natural vegetable oils such as olive oil, sesame oil or paraffin oil or injectable organic esters such as ethyl oleate .
• the sterile aqueous solutions can consist of a solution of a pharmaceutically acceptable salt dissolved in water.
• the aqueous solutions are suitable for intravenous administration as long as the pH is suitably adjusted and the isotonicity is achieved, for example, by a sufficient amount of sodium chloride or glucose. Sterilization can be carried out by heating or by any other means which does not alter the composition.
• compositions according to the invention can contain at least 0.01% of therapeutically active product.
• the amount of active ingredient in a composition is such that a suitable dosage can be prescribed.
• the compositions are prepared in such a way that a unit dose contains from 0.01 to 1000 mg approximately of active product for parenteral administration.
• Therapeutic treatment can be carried out concurrently with other therapeutic treatments including antineoplastic drugs, monoclonal anti-co ⁇ s, immunological therapies or radiotherapies or modifiers of biological responses.
• Response modifiers include, but are not limited to, lymphokines and cytokines such as interleukins, interferons ( ⁇ , ⁇ or ⁇ ) and TNF.
• chemotherapeutic agents useful in the treatment of disorders due to abnormal cell proliferation include, but are not limited to, alkylating agents such as nitrogen mustards such as mechloretamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulfonates such as busulfan, nitrosoureas such as carmustine, lomusine, semustin and streptozocin, triazenes such as dacarbazine, antimetabolites such as folic acid analogs such as methotrexate, pyrimidine analogs such as fluorouracil and cytarabine, purine analogs like mercaptopurine and thioguanine, natural products like vinca alkaloids like vinblastine, vincristine and vendesine, epipodophyllotoxins like etoposide and teniposide, antibiotics like dactinomycin , daunorubicin, doxorubicin, bleomycin,
• the doses used to implement the methods according to the invention are those which allow a prophylactic treatment or a maximum therapeutic response.
• the doses vary according to the form of administration, the particular product selected and the specific characteristics of the subject to be treated. In general, doses are those which are therapeutically effective for the treatment of disorders due to abnormal cell proliferation.
• the products according to the invention can be administered as often as necessary to obtain the desired therapeutic effect. Some patients may respond quickly to relatively large or low doses and may require low or no maintenance doses. Generally, low doses will be used at the start of treatment and, if necessary, increasing doses will be administered until an optimum effect is obtained. For other patients it may be necessary to administer maintenance doses 1 to 8 times a day, preferably 1 to 4 times, depending on the physiological needs of the patient concerned. It is also possible that for some patients it is necessary to use only one or two daily administrations.
• the doses are generally between 0.01 and 200 mg / kg. Intraperitoneally, the doses will generally be between 0.1 and 100 mg / kg and, preferably between 0.5 and 50 mg / kg and, even more specifically between 1 and 10 mg / kg. Intravenously, the doses are generally between 0.1 and 50 mg / kg and, preferably between 0.1 and 5 mg / kg and, even more specifically between 1 and 2 mg / kg. It is understood that, in order to choose the most appropriate dosage, the route of administration, the patient's weight, his general state of health, his age and all the factors which may influence the effectiveness of the treatment must be taken into account.
• Example 2 40 mg of the product obtained in Example 1 are dissolved in 1 cm 3 of Emulphor EL 620 and 1 cm 3 of ethanol then the solution is diluted by adding 18 cm 3 of physiological saline.
• composition is administered by introduction into an infusion of a physiological solution for 1 hour.

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• 1991
  • 1991-07-16 FR FR9108937A patent/FR2679230B1/fr not_active Expired - Fee Related
• 1992
  • 1992-07-14 NZ NZ24354892A patent/NZ243548A/en unknown
  • 1992-07-14 TW TW081105531A patent/TW201740B/zh active
  • 1992-07-14 ZA ZA925245A patent/ZA925245B/xx unknown
  • 1992-07-15 MX MX9204140A patent/MX9204140A/es unknown
  • 1992-07-15 YU YU69892A patent/YU69892A/sh unknown
  • 1992-07-15 IE IE230592A patent/IE922305A1/en not_active Application Discontinuation
  • 1992-07-16 WO PCT/FR1992/000687 patent/WO1993002065A1/fr not_active Application Discontinuation
  • 1992-07-16 JP JP5502629A patent/JPH06509107A/ja active Pending
  • 1992-07-16 SK SK48-94A patent/SK4894A3/sk unknown
  • 1992-07-16 CA CA002113074A patent/CA2113074A1/fr not_active Abandoned
  • 1992-07-16 AU AU23880/92A patent/AU2388092A/en not_active Abandoned
  • 1992-07-16 EP EP92916744A patent/EP0596010A1/fr not_active Ceased
  • 1992-07-16 EP EP92402046A patent/EP0524093A1/fr active Pending
  • 1992-07-16 CZ CS9490A patent/CZ9094A3/cs unknown
  • 1992-07-16 HU HU9400113A patent/HUT66600A/hu unknown
• 1993
  • 1993-12-20 NO NO934723A patent/NO934723L/no unknown
• 1994
  • 1994-01-14 FI FI940191A patent/FI940191A0/fi not_active Application Discontinuation

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